Action Points

Explain to interested patients, that without a clear indication for using erythropoietin in critically ill ICU patients, this study suggests that the drug's use at present should be restricted to randomized trials.

However, the therapy also increased thrombotic events by at least 45%, Howard L. Corwin, M.D., of Dartmouth-Hitchcock Medical Center here, and colleagues, in the multicenter EPO Critical Care Trials Group reported in the Sept. 6 issue of the New England Journal of Medicine.

The findings emerged from a prospective, randomized, placebo-controlled trial, of 1,460 medical, surgical, or trauma patients from 48 to 96 hours after admission to an ICU.

Patients, with a hemoglobin concentration of less than 12 g/dL were recruited from 115 medical centers from December 2003 through June 2006.

Epoetin (40,000 U) or placebo was given weekly, for a maximum of three weeks, and patients were followed for 140 days.

Compared with placebo, epoetin did not decrease either the number of patients who received a red-cell transfusion (relative risk for the epoetin versus the placebo group, 0.95; 95% confidence interval 0.85 to 1.06) or the mean number of red-cell units transfused (4.5 units in the epoetin group and 4.3 units in the placebo group, P=0.42).

However, the hemoglobin concentration at day 29 increased more in the epoetin group than in the placebo group (1.6 g/dL versus 1.2 g/dL, P<0.001).

Mortality tended to be lower at day 29 among patients receiving epoetin (adjusted hazard ratio, 0.79; CI, 0.56 to 1.10). This effect was also seen in prespecified analyses of trauma patients (adjusted hazard ratio, 0.37; CI, 0.19 to 0.72).

A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; CI, 0.65 to 1.13), particularly among the trauma patients (adjusted hazard ratio, 0.40; CI, 0.23 to 0.69).

At least one adverse event occurred in 94% of patients in the placebo group and in 94.8% of those given epoetin.

Similarly 43.5% of patients receiving placebo and 44.0% of those given epoetin had a serious adverse event, such as sepsis, respiratory insufficiency, and multiple organ failure.

On the other hand, compared with placebo, epoetin was associated with a 45% to 55% increase in serious thrombotic events (hazard ratio, 1.41; CI, 1.06 to 1.86).

Post-hoc analysis found that thrombotic vascular events in the epoetin group compared with placebo increased among patients who did not receive heparin at baseline (12.3% versus 10.2%).

In discussing the findings, Dr. Corwin and his colleagues wrote that two previous trials involving critically ill patients showed that treatment with epoetin reduced the number of red-cell transfusions. The present trial found no such reductions, an unexpected finding, possibly caused by the transfusion levels in the older studies versus the newer restrictive transfusions in the current study.

Although the original hypothesis was that the use of epoetin would prevent adverse effects of transfused cells, this was clearly not the case, the researchers said.

The most important finding in the current trial, they said, is the reduction in mortality among patients given epoetin compared with those given placebo, a finding most important for the trauma patients. This decrease suggests that epoetin has actions distinct from hematopoiesis.

The drug, the researchers said, could benefit trauma patients remaining in an ICU for more than 48 hours and who have hemoglobin concentrations below 12 g/dL and no history of thrombotic disease, and providing they meet all other significant criteria.

However, the present study suggests that without further study, epoetin should not be given before a patient has been in the ICU for 48 hours, because early administration may alter the risk-benefit ratio.

Also, they said use of epoetin is not supported for ICU patients with a nontraumatic surgical or medical diagnosis, unless they have an approved indication for epoetin.

Further study is needed to explore the possible mechanisms responsible for these effects, they said. Furthermore, these results increase the concern about thrombotic complications, while the post-hoc heparin analysis suggests that prophylactic heparin could be considered for critically ill patients receiving epoetin alpha.

In an accompanying editorial, Deborah Cook, M.D., and Mark Crowther, M.D., of McMaster University in Hamilton, Ontario, wrote that as this study illustrates, large, rigorous investigations involving vulnerable, critically ill patients are crucial to help inform clinicians about what to do, what to consider, and what to avoid.

"Without a clear indication for initiating erythropoietin in all critically ill patients, new prescriptions for this drug should be restricted to randomized trials with independent research oversight carefully examining fatal and nonfatal clinically important outcomes," they wrote.

This "intriguing trial" should incite some investigators to explain the potential survival benefits of erythropoietin in trauma patients, while others might investigate unanticipated adverse events, they wrote. Clinical investigators may reexamine the risk-benefit ratio for administering erythropoietin to patients with chronic renal failure in the ICU, given their high prevalence of vascular disease.

Large observational studies are also needed of anemia, erythropoietin, transfusions, and myocardial ischemia in patients in the ICU, in whom the biomarker troponin is commonly elevated, conferring an increased risk of death.

Studies of behavioral approaches to blood conservation and restrictive transfusion strategies will also advance this field, they concluded.

The epoetin study was supported by Johnson & Johnson Pharmaceutical Research and Development.

Dr. Howard Corwin reported receiving consulting and lecture fees from Ortho Biotech and Johnson & Johnson Pharmaceutical Research and Development; Other investigators reported receiving fees from Ortho Biotech; Drs. Robert An, Peter Bowers, Paul Burton, and Mark Klausner reported being employees of Johnson & Johnson Pharmaceutical Research and Development; Michael J. Corwin, M.D., reported that he is an employee of BattelleCRO, a paid contractor to Johnson & Johnson Pharmaceutical Research and Development. No other potential conflicts of interest were reported.

The editorial writers reported no potential conflict of interest relevant to this article.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine

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